Phosphorylation of Cdc20/Fizzy negatively regulates the mammalian cyclosome/APC in the mitotic checkpoint

Yana Yudkovsky, Michal Shteinberg, Tamar Listovsky, Michael Brandeis, Avram Hershko*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

The cyclosome/anaphase promoting complex (APC) is a multisubunit ubiquitin ligase that targets mitotic regulators for degradation in exit from mitosis. It is activated at the end of mitosis by phosphorylation and association with the WD-40 protein Cdc20/Fizzy and is then kept active in the G1 phase by association with Cdh1/Hct1. The mitotic checkpoint system that keeps cells with defective spindles from leaving mitosis interacts with Cdc20 and prevents its stimulatory action on the cyclosome. The activity of Cdh1 is negatively regulated by phosphorylation, while the abundance of Cdc20 is cell cycle regulated, with a peak in M-phase. Cdc20 is also phosphorylated in G2/M and in mitotically arrested cells, but the role of phosphorylation remained unknown. Here we show that phosphorylation of Cdc20 by Cdk1/cyclin B abrogates its ability to activate cyclosome/APC from mitotic HeLa cells. A nonphosphorylatable derivative of Cdc20 stimulates cyclin-ubiquitin ligation in extracts from nocodazole-arrested cells to a much greater extent than does wildtype Cdc20. It is suggested that inhibitory phosphorylation of Cdc20/Fizzy may have a role in keeping the cyclosome inactive in early mitosis and under conditions of mitotic checkpoint arrest. (C) 2000 Academic Press.

Original languageAmerican English
Pages (from-to)299-304
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume271
Issue number2
DOIs
StatePublished - 10 May 2000

Bibliographical note

Funding Information:
We thank Clara Segal for skillful technical assistance. This research was supported by a United States–Israel Binational Science Foundation (BSF) grant to A.H. and by BSF and Israel Science Foundation grants to M.B.

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